Furan electrophilic oxidation

Phomactin A is the most challenging family member architecturally. The fragments that are most challenging are highlighted in Fig. 8.4. In Box-A, the highly sensitive hydrated furan is prone to dehydration under acidic or basic conditions, and any total synthesis almost certainly must save introduction of this fragment until the end game. Box-B relates to the strained and somewhat twisted electron-rich double bond. This trisubstituted olefin is extremely reactive toward electrophilic oxidants. 

The observed moderate sitoselectivity of the furan ring oxidation at C-5 was attributed to a coordination of the electrophilic Br" " species with the allylic C-8-OR group, prior to the attack on the aromatic ring (60). 

From the preceding examples it can be seen that oxidants and electrophilic reagents attack pyrroles and furans at positions 2 and 5 in the case of indoles the common point of attack is position 3. Thus autoxidation of indoles e.g. 99) gives 3-hydroperoxy-3H-indoles (e.g. 100). Lead tetraacetate similarly reacts at the 3-position to give a 3-acetoxy-3H-indole. Ozone and other oxidants have been used to cleave the 2,3-bond in indoles (Scheme 30) (81BCJ2369). 

We had two possible routes in which alcohol 72 could be used (Scheme 8.19). Route A would involve rearrangement of tertiary alcohol 72 to enone 76. Deprotonation at C5 and generation of the enolate followed by exposure to an oxaziridine or other oxygen electrophile equivalents might directly afford the hydrated furan C-ring of phomactin A (see 82) via hydroxy enone 81. We had also hoped to make use of a chromium-mediated oxidative rearrangement of tertiary allylic alcohols. Unfortunately, treatment of 72 to PCC produced only unidentified baseline materials, thereby quickly eliminating this route. 

The total synthesis of the furo[3,2-a]carbazole alkaloid furostifoline is achieved in a highly convergent manner by successive formation of the car-bazole nucleus and annulation of the furan ring (Scheme 15). Electrophilic substitution of the arylamine 30 using the complex salt 6a provides complex 31. In this case, iodine in pyridine was the superior reagent for the oxidative cyclization to the carbazole 32. Finally, annulation of the furan ring by an Amberlyst 15-catalyzed cyclization affords furostifoline 33 [97]. 

These compounds are less common than indole (benzo[ ]pyrrole). In the case of benzo[i>]furan the aromaticity of the heterocycle is weaker than in indole, and this ring is easily cleaved by reduction or oxidation. Electrophilic reagents tend to react with benzo[Z ]furan at C-2 in preference to C-3 (Scheme 7.21), reflecting the reduced ability of the heteroatom to stabilize the intermediate for 3-substitution. Attack in the heterocycle is often accompanied by substitution in the benzenoid ring. Nitration with nitric acid in acetic acid gives mainly 2-nitrobenzo[Z ]furan, plus the 4-, 6- and 7-isomers. When the reagent is in benzene maintained at 10 °C, both 3- and 2-nitro[ ]furans are formed in the ratio 4 1. Under Vilsmeier reaction conditions (see Section 6.1.2), benzo[Z ]furan gives 2-formylbenzo[6]furan in ca. 40% yield. 

Many common reactions of aliphatic amines, ethers and sulfides (1) involve initial attack by an electrophilic reagent at a lone pair of electrons on the heteroatom salts, quaternary salts, coordination compounds, amine oxides, sulfoxides and sulfones are formed in this way. Corresponding reactions are very rare (c/. Section 3.3.1.3) with pyrroles, furans and thiophenes. These heterocycles react with electrophilic reagents at the carbon atoms (2-3) rather than at the heteroatom. Vinyl ethers and amines (4) show intermediate behavior reacting frequently at the (3-carbon but sometimes at the heteroatom. 

Pyrroles and furans are particularly easily oxidized. The mechanism of primary attack can be electrophilic, radical or cyclic transition state, and the assignment of individual reactions to these classes is sometimes arbitrary. 

Oxidative ring fission of furans using the commercially available reagent pyridinium chlorochromate (PCC) has been studied as well (80T661). Experimental evidence supports the preliminary formation of intermediate (87) formed by 1,4-electrophilic attack of chlorochromate anion upon the furan ring. This intermediate then breaks down by heterolytic cleavage of the Cr—O bonds to afford initially the cis enedione which isomerizes to the trans product. Treatment of (88) with sodium hydroxide in methanol effects ring closure with formation of the 4-methoxycyclopentenone (89 Scheme 22). 

A DFT study of the reactivity of pyridine and the diazabenzenes towards electrophilic substitution, assuming frontier orbital control of the reactions, predicts their low reactivity as the HOMOs of these substrates are not n-orbitals.5 For pyridine-N-oxide, however, the HOMO is an aromatic orbital. DFT studies giving Fukui indices predict6 the preferred sites of electrophilic attack on pyrrole, furan, and thiophene and calculation of the local softness of the reactive sites rationalizes relative reactivities. 

Electrophilic substitution of the appropriately functionalized arylamine and subsequent iron-mediated oxidative cyclization with aromatization generates the carbazole skeleton. Annulation of the furan ring by treatment with catalytic amounts of amberlyst 15 affords furostifoline directly. Comparison of the six total syntheses reported so far for furostifoline demonstrates the superiority of the iron-mediated synthesis (Table 1 in ref. [43a]). Starting from the 2-methoxy-substituted tricarbonyliron-coordinated cyclohexadienylium salt this sequence has been applied to the synthesis of furoclausine-A (Scheme 15.12) [45]. 

The regioselective nudeophUic attack of the arylamine at the 2-methoxy-substituted iron complex salt is controlled by the methoxy group, which directs the arylamine to the para-position. Moreover, electrophilic attack takes place at the sterically less-hindered orfho-amino position. Iron-mediated oxidative cyclization of the resulting iron complex to the carbazole followed by proton-catalyzed aimulation of the furan ring provides 8-methoxyfurostifoline. Oxidation with 2,3-dich]oro-5,6-dicyano-l,4-benzoquinone (DDQ) to O-methylfurodausine-A followed by deavage of the methyl ether provides furoclausine-A (five steps, 9 % overall yidd). 

Wacker-type reactions are Pd(II)-catalyzed transformations involving heteroatom nucleophiles and alkenes or alkynes as electrophiles [108]. In most of these reactions, the Pd(ll) catalyst is converted to an inactive Pd(0) species in the final step of the process, and use of stoichiometric oxidants is required to effect catalytic turnover. For example, the synthesis of furan 113 from a-allyl-P-diketone 112 is achieved via treatment of the substrates with a catalytic amount of Pd(OAc)2 in the presence of a stoichiometric amount of C uC F [109]. This transformation proceeds via Pd(lt) activation of the alkene to afford 114,... 

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